title: IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF-1.
abstract: Macrophages (MΦs) colonize tissues during inflammation in two distinct ways: recruitment of monocyte precursors and proliferation of resident cells. We recently revealed a major role for IL-4 in the proliferative expansion of resident MΦs during a Th2-biased tissue nematode infection. We now show that proliferation of MΦs during intestinal as well as tissue nematode infection is restricted to sites of IL-4 production and requires MΦ-intrinsic IL-4R signaling. However, both IL-4Rα-dependent and -independent mechanisms contributed to MΦ proliferation during nematode infections. IL-4R-independent proliferation was controlled by a rise in local CSF-1 levels, but IL-4Rα expression conferred a competitive advantage with higher and more sustained proliferation and increased accumulation of IL-4Rα(+) compared with IL-4Rα(-) cells. Mechanistically, this occurred by conversion of IL-4Rα(+) MΦs from a CSF-1-dependent to -independent program of proliferation. Thus, IL-4 increases the relative density of tissue MΦs by overcoming the constraints mediated by the availability of CSF-1. Finally, although both elevated CSF1R and IL-4Rα signaling triggered proliferation above homeostatic levels, only CSF-1 led to the recruitment of monocytes and neutrophils. Thus, the IL-4 pathway of proliferation may have developed as an alternative to CSF-1 to increase resident MΦ numbers without coincident monocyte recruitment.
authors.affiliation: Institute of Immunology and Infection Research, School of Biological Sciences; and 2 Medical Research Council Centre for Inflammation Research and 3 The Roslin Institute and Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine; University of Edinburgh, Edinburgh EH8 9YL, Scotland, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Jenkins
authors.forename: Dominik
authors.initials: D
authors.lastname: Ruckerl
authors.forename: Graham D
authors.initials: GD
authors.lastname: Thomas
authors.forename: James P
authors.initials: JP
authors.lastname: Hewitson
authors.forename: Sheelagh
authors.initials: S
authors.lastname: Duncan
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Judith E
authors.initials: JE
authors.lastname: Allen
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D049109:Cell Proliferation; D005370:Filarioidea / Q000502:physiology; D006369:Heligmosomatoidea / Q000502:physiology; D006706:Homeostasis; D007249:Inflammation / Q000469:parasitology / Q000473:pathology; D015847:Interleukin-4 / Q000378:metabolism*; D007422:Intestines / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008262:Macrophage Activation; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor